heliotrine and dehydroretronecine

Pyrrolizidine alkaloid-containing plants are widespread in the world and may be the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids require metabolism to exert their genotoxicity and tumorigenicity. Our mechanistic studies have determined that metabolism of the retronecine-type (riddelliine, retrorsine, and monocrotaline), heliotridine-type (lasiocarpine), and otonecine-type (clivorine) tumorigenic pyrrolizidine alkaloids in vivo and/or in vitro all generates a common set of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts responsible for tumor induction. All the pyrrolizidine alkaloids studied previously are diesters with an ester linkage at the C7 and C9 positions of the necine base. In this study, we report that F344 rat liver microsomal metabolism of heliotrine, a tumorigenic monoester bearing a hydroxyl group at the C7 of the necine base, resulted in the formation of the dehydroheliotridine (DHH) metabolite. When incubations of heliotrine were carried out in the presence of calf thymus DNA, the same set of DHP-derived DNA adducts was formed. These results support that DHP-derived DNA adducts are potential common biomarkers of pyrrolizidine alkaloid exposure and tumorigenicity. For comparison, the dehydroretronecine (DHR)-derived DNA adducts formed from metabolism of riddleiine, retrorsine, monocrotaline, riddelleiine N-oxide, and retrorsine N-oxide were measured in parallel; the levels of DHP-derived DNA adduct formation were in the order: riddelliine approximately retrorsine>monocrotaline>retrorsine N-oxide>or=riddelliine N-oxide>heliotrine.

Topics: Animals; Biomarkers; Biotransformation; Cattle; Chromatography, High Pressure Liquid; Circular Dichroism; DNA; DNA Adducts; In Vitro Techniques; Isotope Labeling; Male; Microsomes, Liver; Monocrotaline; Pyrrolizidine Alkaloids; Rats; Rats, Inbred F344; Stereoisomerism; Thymus Gland

Female hooded rats were injected intraperitoneally on the 14th day of pregnancy with dehydroheliotridine (DHH), a pyrrolic metabolite of pyrrolizidine alkaloids, at 30 to 90 mg/kg, or with the alkaloid heliotrine at 200 mg/kg and the effects on the embryos were evaluated on the 20th day. DHH was both growth-retarding and teratogenic. A dose of 40 mg DHH/kg approximated 200 mg heliotrine/kg in its effects on embryos, the principal abnormalities being skeletal, including retarded ossification, distorted ribs and long bones, cleft palate and feet defects. At higher dose rates growth almost ceased in many tissues and although more than 60 per cent. of the embryos were alive they would not have survived birth. All were very immature and had multiple skeletal and visceral defects. The effects observed in the liver were anomalous in that the embryonic parenchyma showed little response to the anti-mitotic activity of DHH.

Topics: Abnormalities, Drug-Induced; Animals; Female; Fetal Death; Fetal Growth Retardation; Gestational Age; Monocrotaline; Pregnancy; Pregnancy, Animal; Pyrrolizidine Alkaloids; Rats